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Designing the Optimal Formulation for Biopharmaceuticals: A New Approach Combining Molecular Dynamics and Experiments.

Authors
  • Arsiccio, Andrea1
  • Paladini, Andrea1
  • Pattarino, Franco2
  • Pisano, Roberto3
  • 1 Department of Applied Science and Technology, Politecnico di Torino, 24 corso Duca degli Abruzzi, Torino, 10129 Italy. , (Italy)
  • 2 Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale "A. Avogadro", Largo Donegani 2/3, 28100 Novara, Italy. , (Italy)
  • 3 Department of Applied Science and Technology, Politecnico di Torino, 24 corso Duca degli Abruzzi, Torino, 10129 Italy. Electronic address: [email protected] , (Italy)
Type
Published Article
Journal
Journal of Pharmaceutical Sciences
Publisher
Elsevier
Publication Date
Jan 01, 2019
Volume
108
Issue
1
Pages
431–438
Identifiers
DOI: 10.1016/j.xphs.2018.09.002
PMID: 30222976
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Biopharmaceuticals are often stored in a lyophilized form. However, stresses due to both the freezing and the drying steps of the lyophilization process can be harmful to protein stability, and appropriate excipients must be added to minimize detrimental effects. In this work, molecular dynamics was used to provide insight into the mechanisms of protein stabilization by different osmolytes, using lactate dehydrogenase as model protein. Our simulations indicate that good cryoprotectants are not always equally good as lyoprotectants, suggesting that synergistic effects may arise when different excipients are combined. This observation is in accordance with the experimental results. In fact, the enzymatic activity of lactate dehydrogenase after freeze-drying was investigated for various formulations, and the trend predicted by molecular dynamics was confirmed. More specifically, we found that the most effective stabilization of the protein structure is achieved when a good cryoprotectant is coupled with an efficient lyoprotectant. Ultimately, we propose a new approach to the design of formulations for protein-based therapeutics to be lyophilized, which combines simulations and experiments. In this new concept, the computational investigation allows a more knowledge-driven and targeted experimental campaign for the selection of the optimal excipients, making the whole process extremely time- and cost-effective. Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

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